Efficacy and Safety Study of Disitamab Vedotin + RC148 vs. Albumin-Paclitaxone ± Toripalimab in HR-/HER2-low Breast Cancer

Inclusion criteria

• Voluntarily agree to participate in the study and sign the informed consent form
• Stage III unresectable locally advanced or Stage IV metastatic breast cancer.
• Subjects must be willing and able to provide a tumor tissue block and/or unstained pathology slides, with priority given to the most recent metastatic lesions that have not previously been subjected to radiotherapy. If this is not feasible or available, then a tumor tissue block (or fresh tissue sections) obtained from locally recurrent lesions should be provided. Freshly obtained tissue is preferred over archived tissue. The provided tissue will be used for biomarker testing and must be suitable for analysis of HER2 expression and PD-L1 expression
• Invasive breast tumor tissue has been confirmed as HER2 low expression by the central laboratory
• Invasive tumor tissue is negative for hormone receptors (HR), defined as immunohistochemistry (IHC) testing showing that the proportion of cells with positive nuclear staining for both ER and PgR in invasive cancer is less than 1%. For patients with weakly positive ER/PgR (1% to 10% of tumor cell nuclei positive), those who are not suitable for endocrine therapy after thorough evaluation by the investigator, and with approval from the sponsor after communication, may be included in this study
• For HR-negative, HER2-low expressing unresectable locally advanced or metastatic breast cancer: locally recurrent and unresectable or previously untreated metastatic breast cancer; or those who have completed curative treatment (excluding radiotherapy) (e.g., the date of surgery for the primary breast tumor or the last date of adjuvant therapy administration, whichever is later), with an interval of ≥6 months from the first documented local or distant disease recurrence. For subjects who received taxane drugs during the (neo)adjuvant therapy phase, there must be an interval of ≥12 months from the last taxane administration
• ECOG performance status of 0 or 1
• According to the RECIST v1.1 criteria, there must be at least one measurable lesion (for lesions that have previously been irradiated, if the lesion can be measured according to the RECIST v1.1 criteria and there is evidence of significant progression after radiotherapy, the lesion can be considered a target lesion)
• Expected survival of at least 12 weeks
• Hematologic and organ function criteria to be met within 7 days prior to the first dose of study medication (with normal values based on the clinical trial center's standards, and no blood transfusions, hematopoietic growth factors, albumin, or blood products within 14 days prior to the test):

Hemoglobin ≥ 90 g/L Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L Platelet count ≥ 100 × 10^9/L Total bilirubin ≤ 1.5 × upper limit of normal (ULN) or direct bilirubin ≤ ULN (for subjects with total bilirubin > 1.5 × ULN). Total bilirubin ≤ 3 × ULN (for subjects with Gilbert's disease) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN (if liver metastases are present) International normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN Creatinine clearance (CrCl) calculated by the Cockcroft-Gault formula ≥ 40 mL/min, or serum creatinine ≤ 1.5 × ULN Urine routine test shows urine protein < 2+; if urine protein ≥ 2+, the 24-hour urine protein quantification result must be < 1 g.

• Female subjects of childbearing potential who meet the following conditions:

A serum pregnancy test (with a minimum sensitivity of 25 mIU/mL or equivalent units of β-human chorionic gonadotropin [β-hCG]) must be negative within 7 days prior to the first dose of study intervention. Subjects with a false-positive result that is confirmed not to be pregnant are eligible to participate in the study.

Must agree to use contraception during the study and for at least 6 months after the last dose of study medication. No breastfeeding or egg donation within 6 months.

If sexual activity could lead to pregnancy, they must use at least one acceptable form of contraception from the time of informed consent until at least 6 months after the last dose of study medication.

• Male subjects of childbearing potential who meet the following conditions:

Must agree to abstain from donating sperm from the start of the study until at least 6 months after the last dose of study medication.

If having sexual intercourse with a person of childbearing potential that could lead to pregnancy, must consistently use at least one acceptable form of contraception throughout the study and for at least 6 months after the last dose of study medication.

If having sexual intercourse with a pregnant or breastfeeding partner, must use condoms from the time of informed consent until at least 6 months after the last dose of study medication.

• Capable of understanding the trial requirements and willing and able to comply with the trial and follow-up procedures.

Exclusion criteria

• Having previously received anti-HER2 treatment, including ADC (Antibody-Drug Conjugates).
• Having previously received immunotherapy, including anti PD-(L)1 or anti PD-(L)2 drugs, or drugs that directly target another stimulatory or co-inhibitory T-cell receptor (such as CD137, CTLA-4, OX-40) during the locally advanced or metastatic stage (except if the last administration was ≥12 months prior to recurrence or progression, using [neo]adjuvant anti PD-(L)1).
• Excluding subjects with brain metastases or leptomeningeal metastases. Subjects with treated brain metastases (surgery and/or radiotherapy) are eligible for inclusion if they meet the following criteria:

Subjects who have received treatment for brain metastases may be considered for participation in this study if they have not experienced disease progression as determined by imaging studies within 4 weeks prior to the first dose of study treatment.

They must have discontinued the use of corticosteroids or anticonvulsant therapy at least 14 days before the first dose of study

• Use of investigational drugs or undergoing major surgery within 4 weeks prior to the first dose of study medication
• Received or plan to receive live vaccines or attenuated live vaccines within 4 weeks prior to the first dose of study medication or during the study period
• History of allogeneic hematopoietic stem cell transplantation or organ transplantation
• Uncontrolled or significant cardiovascular or cerebrovascular disease, including (but not limited to):

Within 6 months prior to the first dose of study medication, any of the following occurred: congestive heart failure (NYHA Class III or IV), myocardial infarction, or cerebral infarction (except for lacunar infarction), pulmonary embolism, unstable angina, or the presence of arrhythmias requiring treatment at screening; Primary cardiomyopathy (such as dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, unclassified cardiomyopathy); A history of clinically significant QTc interval prolongation, second-degree type II atrioventricular block or third-degree atrioventricular block, or QTc interval (Fridericia's formula) > 470 msec (females) or > 450 msec (males); Atrial fibrillation (EHRA classification ≥ class 2b); Uncontrolled hypertension, as judged by the investigator to be unsuitable for participation in the study

• Presence of clinically uncontrollable third space fluid accumulation, such as large amounts of pleural effusion, pericardial effusion, or ascites that are associated with clinical symptoms or require symptomatic treatment.
• History of interstitial lung disease that requires treatment or current severe pulmonary disease, including but not limited to active pulmonary tuberculosis, interstitial lung disease, etc.
• A clear history of neurological or psychiatric disorders, either past or present, including epilepsy or dementia, etc.
• Toxicities from previous anti-cancer treatments have not yet recovered to grade 0-1 of the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0), except for alopecia, hyperpigmentation, or other conditions that the investigator deems do not increase the risk to the subject from treatment.
• Persistent grade ≥2 sensory or motor neuropathy.
• Active infections that require systemic treatment:

Active infections requiring systemic treatment within 7 days prior to the first dose, routine antimicrobial prophylaxis is allowed; Positive HIV test results; Patients with active hepatitis B or C (HBsAg positive with detectable HBV DNA levels above the upper limit of normal; HCVAb positive with detectable HCV RNA levels above the upper limit of normal).

• Having active autoimmune diseases within the past 2 years that require systemic treatment (such as corticosteroids or immunosuppressive drugs), except for replacement therapies (such as thyroid hormone, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency).
• Having other malignant tumors within 5 years prior to signing the informed consent form (except for effectively treated non-melanoma skin cancer, cervical carcinoma in situ, localized prostate cancer, stage I endometrial cancer, or other tumors that are considered cured).
• Known hypersensitivity or delayed-type allergic reactions to certain components of Disitamab Vedotin, Toripalimab, RC148, or albumin-bound paclitaxone, or similar drugs.
• According to the investigator's judgment, there are serious concomitant diseases that could endanger the subject's safety or affect the subject's ability to complete the clinical study.